Enteric coated multiparticulate controlled release peppermint oil composition and related methods

ABSTRACT

A multiparticulate composition is formed from a plurality of individual cores including a hydrophobic phase containing peppermint oil dispersed in a microcrystalline cellulose-based gel and a hydrophilic phase containing a hydrogel. An enteric coating is over the individual cores. The multiparticulate composition can be used to treat gastrointestinal disorders.

CROSS-REFERENCE TO RELATED APPLICATION

This is a continuation-in-part of U.S. application Ser. No. 13/367,747,filed Feb. 7, 2012, which claims priority to U.S. provisionalapplication 61/486,523, filed May 16, 2011 and U.S. provisionalapplication 61/441,716, filed Feb. 11, 2011. This also claims priorityto U.S. provisional application 61/815,073, filed Apr. 23, 2013 and U.S.provisional application 61/880,294, filed Sep. 20, 2013. Each of theseprior applications is incorporated by reference in its entirety.

FIELD OF THE INVENTION

The invention relates to enteric coated multiparticulate compositions,and, more particularly, to enteric coated multiparticulate compositionscontaining peppermint oil.

BACKGROUND

Peppermint oil is used to address gastrointestinal problems because itinhibits the smooth muscles in the gastrointestinal tract fromcontracting. Unfortunately, however, if peppermint oil is released inthe stomach, it is absorbed quickly and can upset the stomach. Toovercome this problem, others have developed enteric coated peppermintoil formulations that allow the peppermint oil to pass into theintestines before it is released.

In conventional enteric coated peppermint oil formulations, thepeppermint oil is loaded into a hollow capsule that is enteric coated.The enteric coating prevents the capsule from dissolving in the stomach,but allows the capsule to dissolve in the intestines and release thepeppermint oil.

Single-unit enteric coated peppermint oil capsules such as these haveseveral drawbacks. First, the dose of peppermint oil that is actuallyabsorbed by the intestines of the person taking the capsule isunpredictable. One of the reasons for this is that, when the capsuledissolves, it quickly dumps all of the peppermint oil into the same areaof the intestines, which is problematic because peppermint oil is notvery water soluble. Another of the reasons for this is that food in thegastrointestinal tract affects the amount of peppermint oil absorbed.

A second drawback associated with single-unit enteric coated peppermintoil capsules is that the onset of action of the peppermint oil isunreliable. The primary factor delaying the onset of action is theamount of time the capsule spends in the stomach, which ranges overseveral hours and depends on the amount of food in the stomach. In orderto get a reliable onset of action, one should take the capsules on anempty stomach. But because some gastrointestinal disorders flare upafter a meal, people often want to treat the flare up immediately.Accordingly, the single-unit enteric coated capsules are not ideal fortreating acute gastrointestinal flare ups that are triggered by food.

A third drawback associated with single-unit enteric coated peppermintoil capsules is the fact that peppermint oil is volatile. If thecapsules are shipped or stored much above room temperature for extendedperiods of time, the peppermint oil can evaporate and permeate thecapsule.

We surmised that these problems could be addressed by developing entericcoated multiparticulate compositions containing peppermint oil, butfound that it is difficult to do so because peppermint oil is veryvolatile. If multiparticulate cores containing peppermint oil are heatedor stored for extended periods, much above room temperature, thevolatile components of the peppermint oil leave the cores and permeatethe enteric coating. This made it difficult to process the cores,especially when it came time to cure the enteric coating on the cores atelevated temperatures.

In U.S. patent publication 2012/0207842, we described making entericcoated multiparticulate L-menthol compositions. In order to prevent theL-menthol from sublimating as the cores were being processed, weresorted to low temperature processing techniques. The L-mentholmultiparticulate compositions described in that application provided therelease profile that we desired and worked well for some applications,but were not optimized for all applications.

We have identified a need for a peppermint oil composition that avoidsthe drawbacks associated with single-unit enteric coated capsules andcan be made using conventional room temperature processing techniques

SUMMARY

A multiparticulate composition that embodies these principles comprisesa plurality of individual enteric coated cores that include ahydrophobic phase containing peppermint oil dispersed in amicrocrystalline cellulose-based gel and a hydrophilic phase containinga hydrogel. The microcrystalline cellulose functions as a releasecontrolling polymer for the peppermint oil, preventing dose dumping andstabilizing the peppermint oil while the cores are being processed.

In another composition aspect of the invention, the multiparticulatecomposition comprises a plurality of individual enteric coated corescontaining about 15% w/w to about 40% w/w peppermint oil, about 35% w/wto about 75% w/w microcrystalline cellulose, and about 2% w/w to about15% w/w methylcellulose, wherein the % w/w is the % w/w of the entericcoated cores.

In some cases, including a continuous proteinaceous subcoating layercovering the individual cores and separating the individual cores fromtheir respective enteric coatings may be advantageous because theproteinaceous subcoating layer further enhances the stability of thepeppermint oil. The continuous proteinaceous subcoating is adapted toprevent the peppermint oil from mixing with the enteric coating.

Some preferred proteinaceous subcoatings have the following attributes:the subcoating may comprise a gelatin film adhered to the core and/orthe subcoating may comprise a dried proteinaceous gel.

The enteric coating may have a glass transition temperature higher thana standard boiling point of the peppermint oil.

In a particular embodiment, the enteric coated cores release no morethan about 20% of the peppermint oil within about two hours of beingplaced in a 0.1 N HCl solution and, subsequently, no less than about 85%of the peppermint oil within about eight hours of being placed in asubstantially neutral pH environment.

Preferably, the enteric coated cores are spheroidal and not more than 3mm in diameter.

In a first method aspect of the invention, a method of making amultiparticulate composition comprises blending peppermint oil,microcrystalline cellulose, a hydrogel-forming polymer, and water toform a wet mass including a hydrophobic phase containing the peppermintoil dispersed in a gel formed by the microcrystalline cellulose and ahydrophilic phase containing the hydroxypropyl methylcellulose andwater;

extruding the wet mass to form an extrudate; dividing the extrudate intoindividual wet cores; removing water from the hydrophilic phase in thewet cores to form dried cores; and applying an enteric coating to thedried cores.

The method may further comprise coating the dried cores with a liquidproteinaceous material and drying the liquid proteinaceous material toform sub-coated cores prior to applying the enteric coating. The liquidproteinaceous material may comprises gelatin. A particular example ofthe liquid proteinaceous material is a solution containing at leastabout 50% gelatin.

The dried cores may be coated with the liquid proteinaceous material byspraying the liquid proteinaceous material onto the dried cores.

Once made, the enteric coated cores are preferably spheroidal and notmore than 3 mm in diameter.

Removing water from the hydrophilic phase in the wet cores to form driedcores is preferably achieved without substantially removing peppermintoil.

In a second method aspect of the invention, a method of treating agastrointestinal disorder in a subject comprises administering to thesubject a multiparticulate composition comprising a plurality ofindividual enteric coated cores that include a hydrophobic phasecontaining peppermint oil dispersed in a microcrystallinecellulose-based gel and a hydrophilic phase containing amethylcellulose-based gel. Administering is preferably performedenterally. If desired, the multiparticulate composition may be blendedwith an acidic vehicle prior to being administered.

These and other aspects, embodiments, and advantages of the inventionwill be better understood by reviewing the accompanying figures and theDetailed Description of Preferred Embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the results of an accelerated stability assayfor a multiparticulate composition according to an embodiment of theinvention stored at 40 degrees C. and 75% relative humidity for fourweeks; and

FIG. 2 is a graph showing the results of a two-stage dissolution testfor a multiparticulate composition according to an embodiment of theinvention after the composition was stored at 40 degrees C. and 75%relative humidity.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

In the Summary and Detailed Description of Preferred Embodimentsreference is made to particular features (including method steps) of theinvention. It is to be understood that the disclosure of the inventionin this specification includes all possible combinations of suchparticular features, even if those combinations are not explicitlydisclosed together. For example, where a particular feature is disclosedin the context of a particular aspect or embodiment of the invention,that feature can also be used, to the extent possible, in combinationwith and/or in the context of other particular aspects and embodimentsof the invention, and in the invention generally.

The term “comprises” is used herein to mean that other ingredients,steps, etc. are optionally present. When reference is made herein to amethod comprising two or more defined steps, the steps can be carried inany order or simultaneously (except where the context excludes thatpossibility), and the method can include one or more steps which arecarried out before any of the defined steps, between two of the definedsteps, or after all of the defined steps (except where the contextexcludes that possibility).

In this section, the invention will be described more fully withreference to its preferred embodiments. The invention may, however, beembodied in many different forms and should not be construed as limitedto the embodiments set forth herein. Rather, these embodiments areprovided so that this disclosure will convey preferred embodiments ofthe invention to those skilled in the art.

Because peppermint oil is so volatile, it is difficult to makepeppermint oil-containing dosage forms. Conventional processing methodsfor making pharmaceutical dosage forms involve heating, whichconventional wisdom suggests one should avoid when using volatileingredients. We found that it is very difficult to make stablemultiparticulate peppermint oil-containing compositions, for this andother reasons.

Microcrystalline cellulose, or “MCC,” is a pharmaceutical excipient thatis widely used as a disintegrant in solid oral dosage forms. MCCpromotes the breakup of tablets in aqueous environments to enhance drugrelease. It does this by wicking moisture through the pores of thetablet, weakening the tablet and causing it to disintegrate. Since MCCis used as a disintegrant, its causes the active ingredients in thesolid oral dosage form to be released faster than they would otherwisebe released.

We found that MCC also functions as a release-controlling polymer forpeppermint oil and developed multiparticulate enteric coated peppermintoil compositions using MCC as a release-controlling polymer in the core.The MCC gradually releases the peppermint oil into the intestines ratherthan quickly dumping the entire dose in a small region of theintestines. Accordingly, the MCC in our multiparticulate peppermint oilcompositions performs the opposite function of a disintegrant andovercomes the dose-dumping drawback held by the conventional single-unitenteric coated capsules.

The multiparticulate composition aspect of the inventions is firstdescribed. The multiparticulate composition is adapted to carrypeppermint oil to the intestines and includes a plurality ofparticulates that are preferably spheroidal in shape and are sized tofit through the pyloric sphincter when it is in a relaxed state. Thediameter of each particulate is preferably in the range of about 0.1 mmto about 3 mm or, about 1 mm to about 2.5 mm, or less than about 1.4 mm.Particulates of this diameter are advantageous because they can fitthrough the pyloric sphincter and do not remain in the stomach as longas single-unit capsules, thereby providing a more reliable onset ofaction.

The multiparticulate composition includes a plurality of individualpeppermint-oil containing cores that are each enteric coated. Theenteric coating allows the individual cores to pass through the stomachwithout releasing a substantial amount of peppermint oil. In the pH ofthe intestines, the enteric coating dissolves, exposing the cores andallowing peppermint oil to be released.

The core contains the primary active ingredient peppermint oil, but mayalso contain other secondary active ingredients such as one or moreother terpene-based substances such as terpenes, terpenoids, and/oressential oils. Terpene-based substances that may be used as secondaryactive ingredients include but are not limited to L-menthol, carawayoil, orange oil, ginger oil, turmeric oil, curcumin oil, and fennel oil,among others.

Alternatively, the secondary active ingredient may be anon-terpene-based substance that helps relieve gastrointestinal disordersymptoms from their various actions. Examples of non-terpene secondaryactive ingredients include, but are not limited to, polyphenols such asgreen tea extracts and aloe vera powder, proton pump inhibitors,anti-inflammatories, and immune suppressors among others.

Essential oils such as peppermint oil, caraway oil, orange oil, fenneloil, etc. are liquid at room temperature. They are usually formulated asliquids in a capsule, with an enteric-coating over the capsule. Wediscovered that essential oils can be mixed with a cellulosic filler anda binder to make a dough or wet mass, but the dough formed by simplymixing these materials together does not produce a core with the desiredstrength for subcoating and further processing. By adding water to thewet mass, we produced cores containing peppermint oil that were robustenough for subsequent processing.

The core may also contain one or more antioxidants that can maintain thepurity of the peppermint oil and other active ingredients if used. Thisis useful because peppermint oil can oxidize to form undesirablederivatives. Examples of antioxidants that may be used include, but arenot limited to tocopherol (vitamin E,) BHT (butylated hydroxy toluene),BHA (butylayted hydroxy anisole), and ascorbic acid.

In the core, peppermint oil is combined with MCC and a hydrogel formingpolymer binder such as s a cellulose-based, starch-based, and/orpovidone-based binder. It is to be understood that “cellulose-based,”“starch-based” binders, and “povidone-based” binders includes cellulose,starch, and povidone derivatives. When mixed with water, the binderswells to form a hydrogel matrix. In contrast, MCC and peppermint oilare hydrophobic. Examples of cellulose-based binders includemethylcellulose based polymers, including, for example, methylcelluloseand hydroxypropyl methylcellulose. Methylcellulose is particularlypreferred for use in the composition.

When water is added to the core during processing, these materialsseparate into a hydrophobic phase and hydrophilic phase. The hydrophobicphase contains peppermint oil dispersed in the microcrystallinecellulose-based gel and the hydrophilic phase contains the hydrogel. Thepeppermint oil is therefore, dispersed throughout the hydrophobic phase,which is in contact with the hydrophilic phase.

One of the advantageous of dispersing the peppermint oil in MCC is thatit allows excess water to be removed from the cores without alsoremoving a substantial amount of the peppermint oil. Conventional dryingtechniques would cause the peppermint oil in the core to evaporate withthe water. Thus, by making the core to include a hydrophobic phasecontaining peppermint oil dispersed in a microcrystallinecellulose-based gel and a hydrophilic phase containing amethylcellulose-based polymer, the core can be processed without riskingsubstantial loss of the peppermint oil.

The core may also include pharmaceutically acceptable fillers,stabilizers, binders, surfactants, processing aids, and/ordisintegrants. By way of example only, suitable materials for performingthese functions are provided.

Preferred fillers include cellulosic filler materials such asmicrocrystalline cellulose, dibasic calcium phosphate, and/or anotherpharmaceutically acceptable filler.

Preferred binders include cellulosic water soluble polymers such asmethylcellulose, starch, hydroxypropyl cellulose, gelatin,polyvinylpyrrolidone, polyethylene glycol, and/or anotherpharmaceutically acceptable binder.

In some cases, it may be advantageous to include a surfactant as asolubilizing agent. If used, preferred solubulizing agents include butare not limited to polysorbate and/or sodium lauryl sulfate.Advantageously when polysorbate 80 is used, it may also enhanceabsorption of terpene-based active ingredients into the plasma.

Suitable processing aids include pharmaceutically acceptable processingaids for improving the flowability of the core materials duringprocessing. Preferred processing aids include, but are not limited to,colloidal silicon dioxide, talc, magnesium stearate, stearin, and/oranother pharmaceutically acceptable processing aid.

Preferred disintegrants include, but are not limited to, croscarmellosesodium, polyvinylpyrrolidone (crospovidone) sodium starch glycolate,and/or another pharmaceutically acceptable processing aid.

In a particularly preferred embodiment of the multiparticulatecomposition, the cores contain about 15% w/w to about 40% w/w peppermintoil, about 35% w/w to about 75% w/w microcrystalline cellulose, andabout 2% w/w to about 15% w/w methylcellulose, wherein the % w/w is the% w/w of the enteric coated cores.

Because it is often desirable to be able to ship products innon-refrigerated vehicles and store them for a long period of time, wepreferred for our peppermint oil-containing multiparticulate compositionto be stable when stored at 40 degrees C. and 75% relative humidity,from between 1 day to 30 days, and even longer. This would also beuseful if the multiparticulate composition is distributed in regions inclimate zone IV.

While developing multiparticulate compositions containing terpene-basedactive ingredients, however, we found that volatile ingredientssometimes penetrated the conventional subcoating materials we used toseparate the cores form their enteric coatings. Because of this, theactive ingredients would come in contact with the enteric coating if thetemperature was elevated (25 degrees C.-50 degrees C.) or thecomposition was stored for a long period of time. This somewhat reducedthe effectiveness of the enteric coating and amount of active ingredientin the core.

We solved this problem by developing a new subcoating material that maybe applied to the finished core and prevents volatile active ingredientsin the core from leaving the core and permeating the enteric coating atelevated temperatures. The subcoating includes a proteinaceous materialthat is applied along each core's exterior surface to form asubstantially continuous thin film that forms a barrier between the coreand the enteric coating that is applied after the subcoating.

Examples of proteinaceous materials that may be used in the subcoatinginclude proteins such as, but not limited to casein, whey protein, soyprotein, and various types of gelatin (Type A, Type B or derivatives ofgelatin) or proteinaceous materials that have protein-like structures. Aparticularly preferred material used to form the subcoating is asolution containing at least about 50% of the proteinaceous materialdispersed in a solvent. The solvent is preferably, but not necessarilywater. A particularly preferred proteinaceous material is Type Agelatin.

The proteinaceous subcoating is preferably applied to the core in liquidform and subsequently dried on the core. When dry, the subcoatingadheres to the core. Examples of the liquid form of the proteinaceoussubcoating material include melts and gels. When dry, the subcoatingforms a continuous film over the core and provides a barrier between thecore and enteric coating.

Gelatin typically melts at about 35 degrees C., which is below thenormal human body temperature of about 37 degrees C. Given this, onemight expect that, if a multiparticulate composition, including agelatin subcoating, is heated above 35 degrees C., the subcoating willmelt and release the active ingredients from the core. We observed,however, that gelatin subcoated multiparticulate compositions did notrelease the terpene-based active ingredients from the core even whenheated above 35 degrees C. This is a particularly unexpected result thatprovides numerous advantages.

Because the proteinaceous subcoating prevents volatile peppermint oilfrom being released from the core even when heating above the meltingpoint of the proteinaceous material, by applying the proteinaceoussubcoating, one does not have to avoid heating the subcoated coresduring processing. One scenario in which this is advantageous is whenthe enteric coating is applied. Enteric coating polymers have a glasstransition temperature (T_(g)) that is often above 35 degrees C. Afterbeing applied to a core, enteric coated particulates are preferablyheated above T_(g) so that the enteric coating polymer can cure, therebyachieving optimum enteric protection of the core. Thus, using theproteinaceous subcoating between the core and enteric coating allows oneto achieve optimum enteric protection without releasing the peppermintoil from the core.

The subcoating may be applied to the core as a gelatin-containingsubcoating solution. The solvent may be any solvent in which gelatin issoluble, such as water. In a preferred embodiment, the subcoatingsolution comprises about 5% to about 30% w/w gelatin and about 70% toabout 95% solvent. When the subcoating solution is allowed to dry aroundthe core, the solvent evaporates, leaving a thin gelatin film thatadheres to the core and forms a barrier between the core and entericcoating. The gelatin film subcoating is preferably about 3.5% w/w toabout 35% w/w of the enteric coated particulates. Surprisingly, in ourexperiments, drying the cores containing peppermint oil and water, atabout 15 degrees C. to about 25 degrees C. did not result in significantloss of the peppermint oil as the water was being removed by fluid beddrying.

The enteric coating is applied over each core, or, if a subcoating isused, over the subcoating. In a preferred embodiment, the entericcoating is about 2% w/w to about 35% w/w of the enteric coatedparticulate. A preferred enteric coating material is a methacrylic acidbased material such as a methacrylic acid based co-polymer. Thesematerials may be combined with other materials such as plasticizers forforming an enteric coating solution. In a typical embodiment, theenteric coating solution comprises about 5% w/w to about 35% w/w water,and the enteric-coated dried multiparticulates contain 0.5% w/w to about5% w/w plasticizer, about 0.05% w/w to about 5% w/w anti-adherent, andabout 2% w/w to about 35% w/w methacrylic acid copolymer. By way ofexample only, a suitable plasticizer is triethyl citrate and a suitableanti-adherent is PlasACRYL® T20 (Emerson Resources, Inc., Norristown,Pa.). The enteric coating is preferably about 3.5% w/w to about 35% w/wof the enteric coated particulates.

The enteric-coated particulates may be coated with a finish coat. Thefinish coat is used, for example, to overcome the mucoadhesiveproperties of some enteric coating materials, which make themultiparticulates stick together during processing, storage, ordispensing through a tube for enteral feeding. The finish coat ispreferably a cellulosic derivative such as HPMC (hydroxylpropylmethylcellulose), HPC (hydroxyl propyl cellulose), CMC (carboxymethylcellulose), or another pharmaceutically acceptable finish coatingmaterial. When used, the finish coat is preferably about 1% to 10% w/wof the finished multiparticulate.

A particularly preferred finish coat material is HPMC because is notmucoadhesive. As such, it prevents the multiparticulates from stickingto the stomach wall as well as food in the stomach. This allows themultiparticulates to reach the intestines quickly, making the onset ofaction more reliable than the single-unit capsules.

The release profile of peppermint oil in the body can be varied to treatdifferent disorders. Peppermint oil can be used to treat a plethora ofgastrointestinal disorders such as irritable bowel syndrome,inflammatory bowel disease, gastroparesis, and functional dyspepsia, butit is best to release the active ingredients at a certain point in thegastrointestinal tract to optimally treat each disorder.

To treat gastrointestinal disorders associated with irritable bowelsyndrome, the multiparticulate composition is formulated to minimize theamount of peppermint oil released into the stomach and colon, so thatmost of it is released in the small intestine. Preferably, 20% or lessof the peppermint oil is released into the stomach and 20% or less ofthe peppermint oil is released into the colon. Also, in many instancessuch as IBS, the peppermint oil is preferably gradually released overthe course of about 4 to about 8 hours after the multiparticulates passthe pyloric sphincter into the small intestine in order to deliver theactive ingredients locally in the small intestine. This release profiletreats gastrointestinal disorders by stabilizing the digestive systemand alleviating the symptoms associated with disorders such as irritablebowel syndrome.

To treat a gastrointestinal disorder such as functional dyspepsia(classified as a gastro-duodenal disorder), the multiparticulatecomposition is formulated so that the peppermint oil is rapidly releasedafter the multiparticulates pass through the stomach and the pylorus,over the course of about 0 to about 2 hours in order to deliverpeppermint oil locally to the duodenum section of the small intestine tohelp stabilize the digestive system and/or alleviate the symptomsassociated with functional dyspepsia. Preferably, 20% or less of thepeppermint oil is released in the stomach and 20% or less of thepeppermint oil is released in the jejunum and ileum sections of thesmall intestine (which follow the duodenum) and the colon.

To treat a gastrointestinal disorder such as inflammatory bowel disease,including ulcerative colitis or Crohn's disease), the multiparticulatecomposition is formulated so that the peppermint oil is rapidly releasedafter the multiparticulates pass through the stomach and the smallintestine, over the course of about 4 to about 6 hours, in order todeliver the peppermint oil locally to the colon to attenuate theinflammatory response and/or alleviate the symptoms associated withinflammatory bowel disease. Preferably, 30% or less of the peppermintoil is released in the stomach and small intestine and greater than 70%of the peppermint oil is released in the first 2 hours after themultiparticulates reach the pH of the colon.

In a particularly preferred embodiment, the enteric coated cores of themultiparticulate composition release no more than about 20% of thepeppermint oil within about two hours of being placed in a 0.1 N HClsolution and, subsequently, no less than about 85% of the peppermint oilwithin about eight hours of being placed in a substantially neutral pHenvironment.

It should be understood that where this disclosure makes reference totreating a gastrointestinal disorder, that the terms “treat,” “treating,or any other variation of the word “treat,” include prevention of thegastrointestinal disorder.

The core formulation allows one to achieve a suitable release profilebecause the MCC acts as a release controlling polymer for peppermintoil. One skilled in the art will recognize that that the release rate ofpeppermint oil from the core can be adjusted by including adisintegrant, that actually functions as a disintegrant, or anotherconventional release controlling polymer.

A daily dose of a multiparticulate composition containing peppermint oilis about 20 mg to about 1200 mgs of peppermint oil, split into 2 orthree doses per day. Each dosage form may contain between 10 mgs and 140mgs of peppermint oil, more preferably, about 90-110 mg of peppermintoil.

Doses of the multiparticulate composition may be administeredsporadically when needed for treating acute inflammations of thegastrointestinal tract or may be administered as part of a long termregimen for treating GI disorders such as irritable bowel syndrome,functional dyspepsia, gastroparesis, or inflammatory bowel disease. Atreatment subject may be a human or animal.

The enteric coated multiparticulates may be prepared into a suitablepharmaceutical or medical food dosage form such as a capsule, tablet orsachet, or are mixed with an acidic food vehicle and directly fedthrough a feeding tube. A typical dosage form contains about 400 mg ofthe particulates, but, depending on the desired dosage, this amount maybe adjusted. Acidic food vehicles include citrus juices and foods suchas, for example, apple sauce and apple juice.

The multiparticulate composition is preferably formulated to beadministered enterally, such as orally or through a feeding tube, to ahuman or animal subject to ensure that the subject receives an effectiveamount of peppermint oil over the course of several hours afteringestion. The feeding tube may help with subjects that have achalasia,dysphagia, or another disorder that does not allow them to administer acapsule orally with water. Alternatively the multiparticulates can besprinkled onto apple sauce for patients that cannot swallow larger sizedcapsules.

A preferred method of making the multiparticulate composition is nowdescribed. The core is typically prepared by wet granulating the corematerials into a wet mass, extruding the wet mass to form an extrudate,cutting the extrudate into a plurality of core pieces, and spheronizingthe core pieces. The spheronized core pieces are then dried in a dryersuch as a fluid bed dryer to remove the water. If desired the driedspheronized cores are then sieved to separate cores of different sizes.

The dried spheronized cores are then coated with the proteinaceoussubcoating material if desired. One way to apply the subcoating materialto the cores is to prepare a subcoating solution and spray thesubcoating solution onto the cores. There are various conventionalmethods for doing this, but the preferred method is Wurster coating orfluid bed coating (top spray or bottom spray). The subcoating solutionis subsequently allowed to dry over the cores, leaving each core coatedwith a thin, continuous proteinaceous film. If desired, the subcoatedcores are sieved to separate them into different sizes.

The enteric coating is then applied to the subcoated cores or directlyto the cores if no subcoating is used. One means of applying the entericcoating is to spray it onto the subcoated cores. There are variousconventional methods for doing this, but the preferred method is Wurstercoating or fluid bed coating. The enteric coated particulates aresubsequently dried. During the enteric coating process, the cores arepreferably heated in an environment that is about 20 degrees C. to about50 degrees C. to cure the enteric coating materials above their T_(g).

A finish coating may be applied over the enteric coated particulates ifdesired. One way to apply the finish coating is to spray it onto theenteric coated cores. There are various conventional methods for doingthis, but the preferred method is Wurster coating or fluid bed coating.

A more particular method of making a multiparticulate compositioninvolves blending the peppermint oil, microcrystalline cellulose,hydrogel-forming polymer, and water to form the wet mass. The wet massincludes a hydrophobic phase containing the peppermint oil dispersed ina gel formed by the microcrystalline cellulose and a hydrophilic phasecontaining the hydrogel and water. The wet mass is extruded thenextruded to form an extrudate and the extrudates is divided intoindividual wet cores. Water is removed from the hydrophilic phase in thewet cores to form dried cores. The enteric coating is then applied tothe dried cores.

Another method aspect of the invention is a method of treating agastrointestinal disorder. This method comprises administering to thesubject a multiparticulate composition comprising a plurality ofindividual cores including a hydrophobic phase containing peppermint oildispersed in a microcrystalline cellulose-based gel and a hydrophilicphase containing methylcellulose and an enteric coating over theindividual cores.

The multiparticulate composition can be enterally administered throughuse of a conventional oral dosage form such as a tablet, caplet,capsule, or sachet, among others.

Another enteral means for administering the multiparticulatecomposition, either orally or via a tube, is by adding it to food. Inthis instance, the multiparticulate composition is blended with anacidic food vehicle such as apple juice or another acidic vehicle thatprevents premature release of the active ingredients and is theningested by the subject.

EXAMPLES

This section provides specific examples of the multiparticulatecomposition and method aspects of the invention. These examples areprovided to illuminate certain preferred aspects and embodiments of theinvention, but the scope of the invention is not limited to what theseexamples teach.

Example 1 Preparation of a Multiparticulate Composition

The core was prepared using microcrystalline cellulose (MCC)commercially available under the name AVICEL® PH 102 (FMC Corp.,Philadelphia, Pa.), methylcellulose commercially available under thename METHOCEL® A15LV (Dow Chemical Co., Midland, Mich.), distilledpeppermint oil, and USP purified water.

33.25 kg MCC, 1.75 kg methylcellulose, and 15 kg peppermint oil wereblended with water to form a wet mass. The wet mass was granulated in ahigh shear granulator. The granulated wet mass was then extruded andspheronized. The spheronized particles were subsequently dried in afluid bed dryer to form uncoated cores. The drying temperature was about16 degrees C.

The uncoated cores were Wurster coated with 37 kg of a subcoatingcomposition containing about 15% acid bone gelatin and 85% USP water anddried.

The subcoated cores were Wurster coated with 31 kg of a 20% w/w entericcoating suspension containing KOLLICOAT® MAE 30 DP, PlasACRYL® T20,triethyl citrate USP, and purified water USP. The dry solids weight ofamount KOLLICOAT® MAE 30 DP was approximately 5.4 kg. The dry solidsweight of triethyl citrate was approximately 0.28 kg. The dry solidsweight of PlasACRYL® T20 was approximately 0.5 kg. The enteric coatedcores were then dried at about 40 degrees C.

The enteric coated cores were Wurster coated with 26 kg of a finish coatsolution containing about 10% w/w hydroxyl propyl methyl cellulose and90% water USP and dried at about 40 degrees C.

Example 2 Stability Testing of the Multiparticulate Composition ofExample 1

The multiparticulate composition described in Example 1 was subsequentlytested to ensure that the gelatin subcoating prevented the peppermintoil from evaporating and leaving the core when stored at elevatedtemperatures over a long period of time.

In the first set of experiments, we prepared capsules containing themultiparticulate composition and stored them at degrees C. and 75%relative humidity for four weeks. Each week, we measured the amount ofpeppermint oil in a selection of the capsules. FIG. 1 shows the resultsof this study as a graph of the number of milligrams of L-menthol percapsule as a function of time. The results show that the amount ofL-menthol in the capsules remained more or less constant at about 34 mgduring the four week period. This proves that the gelatin subcoatingmaintains the integrity of the core.

In the second set of experiments, we simulated the gastrointestinalenvironment and measured the dissolution profile of the multiparticulatecomposition to ensure that the enteric coating worked and that almostall of the peppermint oil would be released from the core within about8.5 hours. This was a conventional two stage dissolution study in whichthe sample was placed in an acidic medium (0.1 N HCl) for about twohours and subsequently placed in a neutral medium (pH=6.8) for theremainder of the time.

The results of this experiment are shown in FIG. 2 as the % release ofpeppermint oil, reported as the number of mgs of L-menthol over time.After two hours in the acidic medium, each of the samples tested hadonly released about 10% or less of the peppermint oil, indicating thatthe enteric coating was intact and worked normally. Over the following6.5 hours in the neutral medium, the peppermint oil was graduallyreleased from the core.

Unless otherwise defined, all technical and scientific terms used hereinare intended to have the same meaning as commonly understood in the artto which this invention pertains and at the time of its filing. Althoughvarious methods and materials similar or equivalent to those describedherein can be used in the practice or testing of the present invention,suitable methods and materials are described. The skilled shouldunderstand that the methods and materials used and described areexamples and may not be the only ones suitable for use in the invention.

The specification discloses typical preferred embodiments of theinvention, and although specific terms are employed, the terms are usedin a descriptive sense only and not for purposes of limitation. Theinvention has been described in some detail, but it will be apparentthat various modifications and changes can be made within the spirit andscope of the invention as described in the foregoing specification andin the claims.

That which is claimed is:
 1. A multiparticulate composition comprising aplurality of individual enteric coated cores, the cores including ahydrophobic phase containing peppermint oil dispersed in amicrocrystalline cellulose-based gel and a hydrophilic phase containinga hydrogel.
 2. The multiparticulate composition of claim 1, furthercomprising a continuous proteinaceous subcoating layer covering theindividual cores and separating the individual cores from theirrespective enteric coatings.
 3. The multiparticulate composition ofclaim 2, wherein the continuous proteinaceous subcoating comprises agelatin film adhered to the core.
 4. The multiparticulate composition ofclaim 2, wherein the continuous proteinaceous subcoating comprises adried proteinaceous gel.
 5. The multiparticulate composition of claim 2,wherein the continuous proteinaceous subcoating is adapted to preventthe peppermint oil from mixing with the enteric coating.
 6. Themultiparticulate composition of claim 2, wherein the enteric coating hasa glass transition temperature higher than a standard boiling point ofthe peppermint oil.
 7. The multiparticulate composition of claim 1,wherein the enteric coated cores release no more than about 20% of thepeppermint oil within about two hours of being placed in a 0.1 N HClsolution and, subsequently, no less than about 85% of the peppermint oilwithin about eight hours of being placed in a substantially neutral pHenvironment.
 8. The multiparticulate composition of claim 1, wherein theenteric coated cores are spheroidal and not more than 3 mm in diameter.9. A multiparticulate composition comprising a plurality of individualenteric coated cores containing about 15% w/w to about 40% w/wpeppermint oil, about 35% w/w to about 75% w/w microcrystallinecellulose, and about 2% w/w to about 15% w/w methylcellulose, whereinthe % w/w is the % w/w of the enteric coated cores.
 10. Themultiparticulate composition of claim 9, further comprising a continuousproteinaceous subcoating layer covering the cores and separating thecores from their respective enteric coatings.
 11. The multiparticulatecomposition of claim 10, wherein the continuous proteinaceous subcoatingcomprises a gelatin film adhered to the core.
 12. The multiparticulatecomposition of claim 10, wherein the continuous proteinaceous subcoatingcomprises a dried proteinaceous gel.
 13. The multiparticulatecomposition of claim 10, wherein the continuous proteinaceous subcoatingis adapted to prevent the peppermint oil from mixing with the entericcoating.
 14. The multiparticulate composition of claim 10, wherein theenteric coating has a glass transition temperature higher than astandard boiling point of the peppermint oil.
 15. The multiparticulatecomposition of claim 10, wherein the enteric coated cores release nomore than about 20% of the peppermint oil within about two hours ofbeing placed in a 0.1 N HCl solution and, subsequently, no less thanabout 85% of the peppermint oil within about eight hours of being placedin a substantially neutral pH environment.
 16. The multiparticulatecomposition of claim 9, wherein the enteric coated cores are spheroidaland not more than 3 mm in diameter.
 17. A method of making amultiparticulate composition, the method comprising: blending peppermintoil, microcrystalline cellulose, a hydrogel forming polymer, and waterto form a wet mass including a hydrophobic phase containing thepeppermint oil dispersed in a microcrystalline cellulose gel and ahydrophilic phase containing the hydrogel forming polymer and water;extruding the wet mass to form an extrudate; dividing the extrudate intoindividual wet cores; removing water from the hydrophilic phase in thewet cores to form dried cores; and applying an enteric coating to thedried cores.
 18. The method of claim 17, further comprising coating thedried cores with a liquid proteinaceous material and drying the liquidproteinaceous material to form sub-coated cores prior to applying theenteric coating.
 19. The method of claim 18, wherein the liquidproteinaceous material comprises gelatin.
 20. The method of claim 18,wherein the liquid proteinaceous material is a solution containing atleast about 50% gelatin.
 21. The method of claim 18, wherein coating thedried cores with a liquid proteinaceous material comprises spraying theliquid proteinaceous material onto the dried cores.
 22. The method ofclaim 17, wherein the enteric coated core is spheroidal and not morethan 3 mm in diameter.
 23. The method of claim 17, wherein removingwater from the hydrophilic phase in the wet cores to form dried cores isachieved without substantially removing peppermint oil.
 24. A method oftreating a gastrointestinal disorder in a subject, the method comprisingadministering to the subject a multiparticulate composition comprising aplurality of individual enteric coated cores, the cores including ahydrophobic phase containing peppermint oil dispersed in amicrocrystalline cellulose-based gel and hydrophilic phase containing ahydrogel.
 25. The method of claim 24, wherein administering is performedenterally.
 26. The method of claim 24, wherein the multiparticulatecomposition is blended with an acidic vehicle prior to beingadministered.